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Prostate Cancer

Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin

By: Teemu J. Murtola a b , Tiina Wahlfors c , Antti Haring a , Kimmo Taari d , Ulf-Håkan Stenman e , Teuvo L.J. Tammela a b the PRACTICAL Consortium. Johanna Schleutker c f and Anssi Auvinen g

European Urology, Volume 68 Issue 6, December 2015, Pages 1089-1097

Published online: 01 December 2015

Keywords: Glucose metabolism, Prostate cancer, Risk, Survival

Abstract Full Text Full Text PDF (0,9 MB) Patient Summary

Abstract

Background

Energy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear.

Objective

We explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association.

Design, setting, and participants

The PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database.

Outcome measurements and statistical analysis

Genetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5 × 10−3. Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses.

Results and limitations

A total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p < 0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population.

Conclusions

SNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death.

Patient summary

Genetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes.

Take Home Message

Single-nucleotide polymorphisms in genes involved in the glucose and energy metabolic pathways, especially PDK1 and PGM1 genes, showed consistent associations with serum prostate-specific antigen, risk of high-grade and metastatic prostate cancer, and prostate cancer survival. This evidence supports an important role for glucose metabolism in prostate cancer progression, which could provide new avenues for prevention of prostate cancer death.

Keywords: Glucose metabolism, Prostate cancer, Risk, Survival.

Footnotes

a School of Medicine, University of Tampere, Tampere, Finland

b Department of Urology, Tampere University Hospital, Tampere, Finland

c Institute of Biosciences and Medical Technology / BioMediTech and Fimlab Laboratories, University of Tampere, Tampere, Finland

d Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

e Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland

f Institute of Biomedicine, Medical Biochemistry and Genetics, University of Turku, Turku, Finland

g School of Health Sciences, University of Tampere, Tampere, Finland

Corresponding author. School of Medicine, Building M, Room 313, University of Tampere, PL 2000, 33521 Tampere, Finland. Tel. +358 3 31165015; Fax: +358 3 31164358.

Members of the PRACTICAL Consortium are listed in Supplementary File 1.

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